ABSTRACT The WHO estimates there are approximately 5 million cases of influenza infections annually, with approximately 500,000 deaths occurring globally. The most cost-effective protection against influenza is vaccination. Unfortunately, due to yearly antigenic shifts and drifts, current seasonal vaccines are ineffective. There is a need for a better flu vaccine. In order to design a better flu vaccine, we plan on optimizing the immune synapse using nano/microparticles (MPs) fabricated from the polymer acetalated dextran (Ac-DEX). Our previous data has shown a dependence of particle degradation and optimal immune response against an influenza antigen. Not only does the release of the antigen effect the immune response, the release of the adjuvant is also important. The optimized degradation of both adjuvant and antigen has a drastic change in survival compared to non- optimized formulations. Our particle system is unique because it relies on the highly tunable polymer Ac-DEX. Ac-DEX is ideal for delivery of agents to phagocytic cells because it is acid-sensitive and has significantly increased degradation in the low acid (~pH 5) of the phagosome. In addition to this it has tunable degradation rates that can range from hours to months, which is a unique range from commonly used polyesters (e.g. poly(lactic-co-glycolic acid) (PLGA)) that have degradation on the order of months. Moreover, Ac-DEX is unique from polyesters because its degradation products are pH neutral, and do not have the potential to shift the local pH or damage sensitive payloads. We have three specific aims exploring various optimizations of our particle system. Aim 1 is focused on formulation of the polymer and particles. The release rate of the adjuvant will be explored. Ac-DEX polymer with various cyclic acetal coverages will be fabricated to degrade over a broad range of times. In Aim 2 we will evaluate the effect of loading of a novel influenza antigen either on the surface or encapsulated into the MPs. We will explore degradation rates on antigen release as well as delivery routes in determining the optimal delivery of influenza antigens that provide a broad range of protection. In Aim 3 we will explore our optimized system in protecting ferrets. Ferrets are the ideal large animal model for influenza infection. Using this model, we will evaluate the vaccine efficacy of our formulation, in comparison to a commercially available flu vaccine.